Dextropropoxyphene

Identification

Name

Dextropropoxyphene

Accession Number

DB00647 (APRD00548)

Type

Small Molecule

Groups

Approved, Illicit, Investigational, Withdrawn

Description

Dextropropoxyphene is an analgesic in the opioid category, patented (1955) and manufactured by Eli Lilly and Company. It is intended to treat mild pain and also has antitussive and local anaesthetic effects. The drug has been taken off the market in Europe and the US due to concerns of fatal overdoses and heart arrhythmias. An estimated 10 million patients have used these products.

The drug is often referred to as the general form, "propoxyphene", however only the dextro-isomer (dextropropoxyphene) has any analgesic effect. The levo-isomer appears to exhibit a very limited antitussive effect.

Pharmacology

Propoxyphene, a synthetic opiate agonist, is structurally similar to methadone. Its general pharmacologic properties are those of the opiates as a group. The analgesic effect of propoxyphene is due to the d-isomer, dextropropoxyphene. It binds to the opiate receptors and leads to a decrease of the perception of pain stimuli. Propoxyphene possesses little to no antitussive activity and no antipyretic action.

Mechanism of action

Propoxyphene acts as a weak agonist at OP1, OP2, and OP3 opiate receptors within the central nervous system (CNS). Propoxyphene primarily affects OP3 receptors, which are coupled with G-protein receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine, and noradrenaline is inhibited. Opioids such as propoxyphene also inhibit the release of vasopressin, somatostatin, insulin, and glucagon. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.

The major route of metabolism is cytochrome CYP3A4 mediated N-demethylation to norpropoxyphene, which is excreted by the kidneys.
In 48 hours, approximately 20% to 25% of the administered dose of propoxyphene is excreted via the urine, most of which is free or conjugated norpropoxyphene.

Half life

6-12 hours

Clearance

2.6 L/min

Toxicity

Coma, respiratory depression, circulatory collapse, and pulmonary edema. Seizures occur more frequently in patients with propoxyphene intoxication than in those with opiate intoxication. LD50=230mg/kg (orally in rat, Emerson)

Taxonomy

Description

This compound belongs to the class of organic compounds known as stilbenes. These are organic compounds containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are derived from the common phenylpropene (C6-C3) skeleton building block. The introduction of one or more hydroxyl groups to a phenyl ring lead to stilbenoids.